We created fusion chimeras between GR and the retinoic acid receptor (RAR) that manifest ligand dependent cytoplasmic/nuclear translocation for the chimeric receptor in response to retinoic acid. These chimeras serve as potential reagents for high throughput screening for new ligands. The approach has been extended with the development of a GR/ER chimera that manifests translocation in response to estrogens. We believe that this approach can be generalized to many members of the nuclear receptor super-family, opening a new avenue for ligand discovery.We developed cell lines in which the expression of fluorescently tagged receptors is repressed by chromatin silencing. Addition of HDAC inhibitors or inhibitors of methylation to these cells activates expression of the chimeras, with the resultant development of highly fluorescent cells. This finding provides a potential screen for inhibitors of gene silencing. Preliminary chemical libraries screens have identified agents that overcome gene silencing and thus serve as new candidates for drug development.